Penicillin-aspirin tablets



United States Patent 2,768,115 PENICILLIN-ASPIRIN TABLETS Frank H. Buckwalter, Dewitt, and Alphonse P. Granatek, Syracuse, N. Y., assignors to Bristol Laboratories Inc., Syracuse, N. Y., a corporation of New York No Drawing. Application November 2, 1951-, Serial No. 254,651

5 Claims. (Cl. 167-82) The present invention relates to a new therapeutic product. More particularly, the present invention relates to new pharmaceutical preparations containing penicillin and aspirin and/or an antihistamine which are stable over long periods of time.

The instability of penicillin-aspirin compositions is well known in the pharmaceutical art. For this reason, stable preparations containing these ingredients have not been known and have previously been considered an impossibility. As a result, both the medical profession and the patient have been inconvenienced by the necessity of handling these drugs in separate form. Although some penicillin-aspirin preparations have been proposed previously, these have had all the expected disadvantages of an inferior shelf-life, usually considerably less than four weeks. It is obvious then, that a stable preparation of penicillin and aspirin and antihistamines retaining its original therapeutic activity, and therefore having utility over long periods, is highly desirable from a commercial standpoint, and much needed by the medical profession for the symptomatic treatment of the common cold, and other infections.

Drugs for the symptomatic treatment of the symptoms of colds, allergies, and infections may also be included in these penicillin tablets. Examples of such drugs are the other antipyretics, such as phenacetin, and the various xanthines such as caffeine. 1

The use of antihistamines for the relief of the symptoms of colds, etc. is well known in the art. Therefore a stable preparation containing aspirin, penicillin and antihistamine would be of great therapeutic value in this field.

An object of this invention is to provide stable prep'arations containing penicillin and aspirin.

Another object of the invention is to provide a stable preparation containing penicillin, aspirin and an antihistamine.

Other objects of this invention will become apparent hereinafter.

The objects of the present invention have been accomplished and stable penicillin-aspirin and penicillinaspirin-antihistamine preparations have been obtained by providing a process for the preparation of tablets containing these ingredients.

The amounts of the active ingredients may vary and will be selected by an experienced chemist or pharmacist with regard for the intended use of the preparation. Usually, from 50,000500,000. units of penicillin per tablet and 1 to 5 grains aspirin per tablet are within this range. From 1 to 100 rn'gm. of an antihistamine per tablet is usually satisfactory, as is to 200 mgms. acetophenetidin and 20 to 50 mgms. calfeine.

The composition is not limited to the exact ingredients described to the exclusion of all others, since various other ingredients, while not necessary, may be added if desired. For instance, desoxyephedrine, benzedrine, atropine, ep'hedrine, ascorbic acid, sodium citrate, phenol- 2,768,l l5 Patented Oct. 23, 1956 EXAMPLE I Procaine penicillin centers for tablets To grams of #200 mesh procaine penicillin G were added gm. of pulverized CaCOs-starch and 1 gm. of magnesium stearate. These ingredients were well mixed, slugged and made #20 mesh. Another 1 gm. of magnesium stearate and 90 gm. of corn starch were added and the whole mixed and tableted using /s" deep concave punch. Each tablet weighed 0.31 gm.

The centers were waterproofed by making a ball out of one teaspoonfnl of peanut oil and corn starch, placing the ball in the coating pan with the centers and rotating for about five minutes. Simple syrup, U. S. P., was then added while rotating and the centers dusted immediately with powdered acacia, and dried with an air blower. This syrup-acacia coating was repeated twice more and the coatedtablets dried overnight at 100 F. I

These centers were used in the preparation of the following tablets.

EXAMPLE II Seventy centers of Example I were coated with simple syrup and dusted with pulverized aspirin until .32 g. of aspirin was added per tablet. The tablets were dried overnight at 100 F., finished using simple syrup and powdered sugar' dusting, and dried again overnight at 100 F. The finished Weight of the tablet was .8 g. V

7 Stability data Original assay-94,560 units] EXAMPLE III A suspension of 11' g. of #30 mesh 2-benzylphenoxy- N,N-dimethylethylamine.dihydrogen citrate in 40 cc. of simple syrup, U. S. P., was prepared. This suspension was added to 70 centers of Example I until tablet weight was .495 g. The tablets were then dried at 100 F. overnight.

Simple syrup was again added to the tablets in a coating pan and dusted with pulverized aspirin until g. of aspirin was added per, tablet. The tablets were dried overnight at 100 F.

The tablets were then'finished'using simple syrup and powdered sugar dusting and dried overnight at 100 F. The finished weight of the tablet was 0.95 g.

Stability data [Original assay--89,000 units] EXAMPLE IV The same procedure and ingredients were used as in Example III except that N 4 chlorobenzyl N,N di methyl-N-2-pyridylethylenediamine monohydride was used instead of 2 benzylphenoxy-N,N dimethylethylamine dihydrogen citrate. The finished weight of the tablet was 1.3 g.

EXAMPLE V The same procedure and ingredients were used as in Example III but neoantergan was used instead of 2-benzylphenoxy-N,N-dimethylethylamine dihydrogen citrate. The finished weight of the tablet was 1.2 g.

EXAMPLE VI The same procedure was usedhere as in Example III but Neohetramine was used instead of 2-benzylphenoxy- N,N-dimethylethylamine dihydrogen citrate. The finished weight of the tablet was 1.2 g.

EXAMPLE VII Seventy centers of Example I were coated with a suspension of 11 g. of 2-benzylphenoxy-N,N-dimethylethylamine dihydrogen citrate in 40 cc. of simple syrup until tablet weight was .495 g. The tablets were dried overnight at 100 F.

The tablets were coated with simple syrup in a coating pan and dusted with a mixture of 15.96 g. of pulverized aspirin, 2.1 g. of #60 mesh caffeine, and 10.5 g. of #60 mesh phenacetin until .35 g. of this mixture was added per tablet and the tablets were dried overnight at 100 F.

The tablets were finished using simple syrup and powdered sugar dusting and again dried overnight at 100 F. The finished weight was 1.1 g.

EXAMPLE VIII Eleven grams of N-4-chlorobenzyl-N-dimethyl-N-Z- pyridylethylenediamine monohydride was suspended in 40 cc. of simple syrup. This suspension was added to 70 centers prepared as in Example I until the tablet weight was .495 g. The tablet was dried at 100 F. overnight.

The tablets were then coated with simple syrup in a coating pan and dusted with a mixture of 15.96 g. of pulverized aspirin, 2.1 g. of #60 mesh caflFeine and 10.5 g. of #60 mesh phenacetin until .35 g. of this mixture was added per tablet. The tablets were again dried overnight at 100 F. and finished using simple syrup and powedered sugar dusting and dried at 100 F. overnight. The finished weight was 1.05 g.

EXAMPLE IX The same method and ingredients were used as in Example VII except that Neoantergan was used instead of 2-benzylphenoxy-N,N-dimethylethylamine dihydrogen citrate. The finished weight of the tablet was 1.1 g.

EXAMPLE X The same method and ingredients were used as in Example VII except that Neohetramine replaced 2-benzyl phenoxyN,N-dimethylethylamine dihydrogen citrate.

The finished weight of the tablet was 1.23 g.

EXAMPLE XI Simple syrup was added to 50 centers of Example I in a coating pan and dusted with a mixture of 15.96 g. of pulverized aspirin, 2.1 g. of #10 mesh caffeine, and 10.5 g. of #60 mesh phenacetin until .35 g. of this mixture was added per tablet. The tablets were then dried overnight at 100 F.

The tablets were finished using simple syrup with powdered sugar dusting. The finished weight was 0.9 g. The tablets were then dried at 100 F. overnight.

Stability data [Original assay-87,000 units] 56 0. Loss, 37 C. Loss, Room Loss,

percent percent temp. percent lmonth 86,000 1 2 months 75, 500 13. 2 months 6,000 90 THE DECOMPOSITION OF ASPIRIN Percent 2 months at 56 C 4 2 months at 37 C 2.4 4 months at 37 C 2.2

EXAMPLE XII Pulverized procaine penicillin G (5720 grams) is mixed intimately with 2,756 grams of calcium carbonatestarch granulation, 52 grams of #60 mesh magnesium stearate and 2132 grams corn starch. The mixture is slugged, made #14 mesh and tableted using semi- /32 deep concave punches. Each tablet weighs 205 milligrams and is no more than 0.125 inch thick. The tablets are placed in a coating pan and 512 cc. of peanut oil are adsorbed onto the tablets while they are rotated in the coating pan in a stream of hot air.

The tablets are then coated with a solution of 142.5 grams acacia dissolved in 1425 grams of hot syrup-9% starch suspension, strained through cheesecloth and held at C. The syrup is previously prepared by dissolving 9454 grams granuated sugar in 4727 grams of water, bringing to the boil and mixing in 1415 grams starch. The tablets now weigh about 235 milligrams.

The tablets are dampened with syrup-9% starch (a total of 1050 cc. is used) and 60 mesh 2-benzylphenoxy- N,N-dimethylethylamine dihydrogen citrate (a total of 1480 grams is applied in all) is dusted on. Each application is dried thoroughly in a current of warm air after uniform coverage has been assured by rolling. Each tablet weighs about 277 milligrams.

Two coats of syrup-9% starch suspension (191 cc. each) are applied with thorough air-drying at 43 C. The tablets now weight 286 milligrams.

Aspirin (9317 grams, powdered U. S. P. 80 mesh), cafieine (1863 grams, powdered U. S. P.), phenacetin (7462 grams, powdered U. S. P.) and starch (1863 grams) are mixed thoroughly and passed through a 60 mesh. screen. This APO-starch mixture (19,975 grams) is applied to the previously prepared tablets as dusting powder, using 9300 cc. of the syrup-9% starch suspension as the wetting agent. Larger portions of the latter are required at the end than in the beginning; the point is to completely cover the tablets with the wetting agent and then cover with dusting powder. In each application after rolling until covered, the tablets are dried in a blast of warm air (43 C.). The tablets now weight about 790 milligrams.

Simple syrup is prepared from twelve pounds of sugar, six pounds of water. Powdered acacia grams) is dissolved in 1000 cc. of this syrup and the solution is app d o the tablets in four equal portions, with hot air drying between applications. The tablets now weight about 860 milligrams and are finished with 3000 to 4300 cc. of simple syrup to weight about 870-900 milligrams. The tablets are now waxed and polished in the usual manner. The tablets disintegrate in artificial gastric juice at 37 C. (shaking every minutes) in 45 minutes or less.

EXAMPLE XIII To 1500 grams of procaine penicillin (G) pulverized, was added 1439 grams of CaCOs-starch and 61.0 grams of magnesium stearate. These ingredients were mixed well, passed through a #30 mesh screen, slugged, made #14 mesh and tableted using deep concave punch. Each tablet weighed 0.2 gram. The tablets were placed in a coating pan, and 250 cc. of peanut oil were absorbed onto the tablets while rotating in the coating pan. The tablets were then coated with simple syrup and dusted with acacia until the weight equaled 0.235 gram, dried at 80 F. for three hours and then dried in the air (no heat) for 2 days. The final weight was 0.232 gram.

Ten thousand of these waterproofed centers (wt.- 0.232 g.) were coated with simple syrup using a 2- benzylphenoxy-N,N-dimethylethy]amine dihydrogen citrate #60 mesh as a dusting powder until the tablet weight was 0.263 gram. Two more coats of simple syrup were added and then followed a coating using simple syrup and #60 mesh aspirin dusting powder until the tablet was 0.659 gram. Two more coats of simple syrup with acacia dusting were added and then simple syrup to smoothen the tablets. The weight was 0.71 gram. A very hot air source (l00150 F.) was used throughout the work. The tablets were then cooled, waxed and polished according to usual coating procedure. The final weight was 0.82 g.

Neoantergan is the trade name of pynanisamine mal-eate or N,N dimethyl-N-(p-methoxybenzyl)-N'-(2-pyridyl)- ethylenediamine maleate. Neohetramine is thonzylamine or N,N dimethyl N (p-methoxybenzyl) -N'-(2 pyrimidyl)ethylenediamine. The 2 benzylphenoxy N,N dimethylethylamine dihydrogen citrate may be prepared as follows:

To a well-stirred solution of 184 grams (1.0 mole) of a mixture of approximately equal amounts of 2-benzylphenol and 4-benzylphenol in 650 ml. of toluene is added 46 grams (1:15 moles) of flake sodium hydroxide. The mixture is boiled under reflux until 18 ml. of water has been removed by means of a Dean-Stark trap. \Approximately two hours are required to completely remove the water. If desired, the water may be removed by azeotropic distillation with the toluene, provided the toluene thus lost is replaced. The mixture is filtered through a fnitted glass tunnel of coarse porosity while still hot in order to remove the insoluble sodium 4-benzylphenoxide. Acidification of the sodium 4-benzylphenoxide gives crude 4-benzylphenol, which may be recovered as a byproduct.

A suspension of 86.5 grams (0.6 mole) of beta-dimethylaminoethyl chloride hydrochloride in 100 ml. of toluene is cooled in a beaker and a solution of 30 g. (0.75 mole) of sodium hydroxide in 30 ml. of water is added in one portion. The mixture is stirred until all of the salt has decomposed to form a homogeneous paste on the bottom of the beaker. The toluene solution of the basic chloride is removed by decantation. The aqueous paste is extracted by decantation with five 40 ml. portions of toluene. The combined extracts are dried over anhydrous potassium carbonate for at least two hours.

The dark brown toluene solution of sodium 2-benzylphenoxide is placed in a three-necked flask equipped with a mechanical stirrer and a reflux condenser. The toluene solution of the beta-dimethylaminoethyl chloride is filtered and added to the flask in one portion. The stirred mixture is refluxed overnight. T o the stirred reaction mixture is added a solution of 135 g. (0.7 mole) of anhydrous citric acid in 350 ml. of water. Heat is evolved and the dihydrogen citrate begins to precipitate in a short time. The mixture is cooled and the crude salt collected by filtration. It may be recrystallized from either water or methanol. One recrystallization from water gives 158 g. of 2-benzylphenyl beta-dimethylaminoethyl ether dihydrogen citrate, M. P. 1385-1395 C.

The N 4 chlorobenzyl N',N'-dimethyl-N-2-pyridylethylenediamine monohydride may be prepared as followsu To a stirred mixture of 95.1 g. (1 mole) of 2-aminopyrirnidine, 26 g. (0.31 mole) of sodium bicarbonate and 370 ml. of water heated in a water-bath at -100 C. was added dropwise 3 1.7 g. (0.25 mole) of benzyl chlon'de over a period of thirty minutes. Heating and efficient stirring were continued for 3.5 hours. Cooling caused the product to separate as yellow granules, which were collected by suction and washed on a filter with 600-700 ml. of cold water. The material was dissolved in boiling denatured alcohol, treated with decolorizing charcoal, then filtered and diluted with an equal amount of hot water. The colorless crystals, which formed in the chilled solution were collected and dried; M. P. 80-81 C.; weight 27.6 g. After two recrystallizations from alcohol the compound melted at 8 384 C.

Analysis:Calculated for CuHnNs: C-7l.3%; H- 5.98%. 'Found:C-71.19% and 71.16% and H6.37% and 6.24%.

-A mixture of 37.0 g. (0.2 mole) of recrystallized 2- benzylaminopyrimid-ine, 4.6 g. of lithium amide and ml. of dry toluene was protected from moisture by a calcium chloride tube filled with anhydrous calcium sulfate and refluxed for 24 hours. Ammonia was evolved. To a stirred cold solution of 28. 2 g. (0.63 mole) of sodium hydroxide in '50 ml. of water covered with 150 ml. of toluene was added 57.6 g. (0.4 mole) of beta-dimethylaminoethyl chloride hydrochloride. The toluene extract was washed twice with water, once with a saturated solution of sodium chloride, and shaken for two hours over anhydrous potassium carbonate. This filtered solution was added to the suspension of lithium compound and refluxed for 25 hours. The suspension was warmed, filtered by suction and the pale yellow residue was washed with hot toluene followed by ether and discarded. The filtrate and washings were combined, washed twice with water, once with saturated sodium chloride solution, and dried over potassium carbonate. The mixture was then distilled. The resulting product was a pale yellow oil, boiling point 147-- 149 C./1-2mm.; yield 42.7 g. (83%).

AnaIysis.Calculated for C15H2QN4: C70.3%; H 7.86%. 'Found: C-69.80% and 69.74%; H-7.'83% and 7.68%.

The simple syrup as used herein, is simple syrup U. S. P. However, it is understood that concentrations above or below the U. S. P. can be used in this invention.

The invention is not to be limited to the exact details of operation or exact compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore limited only by the scope of the appended claims.

We claim:

1. A therapeutic tablet, which is stable over long periods of time and which is adapted for oral ingestion, having a solid center comprising a therapeutically eflective, water-insoluble salt of penicillin, said center being separated from the adjoining concentric layer by a film of liquid unsaturated vegetable oil, and having at least one concentric outer layer comprising aspirin, said aspirin being thus excluded from intimate contact with said salt of penicillin.

2. A therapeutic tablet, which is stable over long periods of time and which is adapted for oral ingestion, having a solid center comprising a therapeutically effective, water-insoluble salt of penicillin, said center being separated from the adjoining concentric layer by a film of liquid unsaturated vegetable oil, and having at least one concentric outer layer comprising aspirin, said aspirin being thus excluded from intimate contact with said salt of penicillin, the said concentric outer layer comprising also phenacetin and catfein.

3. A therapeutic tablet, which is stable over long periods of time and which is adapted for oral ingestion, having a solid center comprising a therapeutically effective, water-insoluble salt of penicillin, said center being separated from the adjoining concentric layer by a film of liquid unsaturated vegetable oil, and having at least one concentric outer layer comprising aspirin, said aspirin being thus excluded from intimate contact with said salt of penicillin, the said concentric outer layer comprising also an antihistamine.

4. A therapeutic tablet, which is stable over long periods of time and which is adapted for oral ingestion, having a solid center comprising a therapeutically effective, water-insoluble salt of penicillin, said center being separated from the adjoining concentric layer by a film of liquid unsaturated vegetable oil, and having at least one concentric outer layer comprising aspirin, said aspirin being thus excluded from intimate contact with said salt of penicillin, the said concentric outer layer comprising also phenacetin, caffeine and an antihistamine.

5. A therapeutic tablet, which is stable over long periods of time and which is adapted for oral ingestion, having a solid center comprising a therapeutically efiective, water-insoluble salt of penicillin, said center being separated from the adjoining concentric layer by a film of liquid unsaturated vegetable oil, and having at least one concentric outer layer comprising aspirin, said aspirin being thus excluded from intimate contact with said salt of penicillin, the said concentric outer layer comprising also phenacetin, caffeine and 2-benzylphenyl betadimethylaminoethyl ether dihydrogen citrate.

References Cited in the file of this patent UNITED STATES PATENTS 207,013 Carter Aug. 13, 1878 312,041 Upjohn Feb. 10, 1885 462,990 Oppenheimer Nov. 10, 1891 1,161,690 Kawai Nov. 23, 1915 2,134,714 Glassman Nov. 1, 1938 2,410,110 Taylor Oct. 29, 1946 2,438,106 Alburn Mar. 23, 1948 2,464,053 Omohundro Mar. 8, 1949 2,530,372 Bohls Nov. 21, 1950 2,533,066 Taplin Dec. 5, 1950 2,566,200 Hickey Aug. 28, 1951 2,585,239 Granatek Feb. 12, 1952 OTHER REFERENCES J. A. Ph. A., Pract. Pharm. Ed., March 1948, page 191, column 1.

J. A. Ph. A., September 1948, page 562.

J. A. Ph. A., Pract. Pharm. Ed., January 1950, page 50.

Strong Cobb celet. Drug and Cosmetic Industry, October 1948, page 431.

Upjohn Company, The Odyssey of Modern Drug Research, January 1951, pages 17 to 20.

Gutman: Modern Drug Encyclopedia, 1934, page 221, Silosan Compound.

I. A. Ph. A., Pharmaceutical Abstracts, January 1946, page 24, Oral Penicillin. 

5. A THERAPEUTIC TABLET, WHICH IS STABLE OVER LONG PERIODS OF TIME AND WHICH IS ADAPTED FOR ORAL INGESTION, HAVING A SOLID CENTER COMPRISING A THERAPEUTICALLY EFFECTIVE, WATER-INSULUBLE SALT OF PENICILLIN, SAID CENTER BEING SEPARATED FROM THE ADJOINING CONCENTRIC LAYER BY A FILM OF LIQUID UNSATURATED VEGETABLE OIL, AND HAVING AT LEAST ONE CONCENTRIC OUTER LAYER COMPRISING ASPRIN, SAID ASPIRIN BEING THUS EXCLUDED FROM INTIMATE CONTACT WITH SAID SALT OF PENICILLIN, THE SAID CONCENTRIC OUTER LAYER COMPRISING ALSO PHENACETIN, CAFFEINE AND 2-BENZYLPHENYL BETADIMETHYLAMINOETHYL ETHER DIHYDROGEN CITRATE. 